The following description provides a summary, of information, and is not an admission that any of the information provided or publications referenced herein is prior art to the present disclosure.
Interleukin 6 (IL-6) belongs to cytokine family, characterized by a long chain four-helix bundle structure. Other members of this family include IL-11, IL-17, IL-27, oncostatin-M (OSM), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1) and cardiotrophin like cytokine (CLC). IL-6 is produced by B cells, T cells, monocytes, fibroblasts and other cell types and has both pro- or anti-inflammatory properties. It plays pleiotropic roles in a wide range of biological activities including normal cell inflammatory processes, host immune defense mechanisms, and modulation of cellular growth. It is also involved in the proliferation and differentiation of various malignant tumor cells (Guo, Y., et al., Cancer Treatment Reviews, 2012. 38:904-910). Under some acute inflammatory conditions, its concentration can dramatically increase from pg/ml to μg/ml (Waage, A., et al, Clinical Immu and Immunpath, 1989. 50:394-398).
IL-6 activates cells by binding to the non-signaling IL-6 receptor, present on the cell membrane. This ligand-receptor complex then binds to the signal transducing protein, gp130, and activates the janus tyrosin kinase (JAK), resulting in activation of downstream signal transducers and activators of transcription protein 3 (STAT3) signaling pathway (Heinrich, P. C., et al., Biochem J., 1998. 334:297-314). IL-6 also activates the mitogen activated protein kinase (MAPK) pathway (Heinrich, P. C., et al., Biochem J., 2003. 374: 1-20). IL-6R is expressed as a membrane bound protein in only a few cell types, including hepatocytes, neutrophils, monocytes/macrophages and some lymphocytes whereas gp130 is expressed ubiquitously in all cell types and acts as a signaling protein for other members of the IL-6 cytokine family. The IL-6 signal transduction via membrane bound IL-6R is known as the classical signaling pathway in literature. In addition to the membrane bound IL-6R, a soluble form of IL-6R (sIL-6R) is present in high concentration in blood and other body fluids (Honda 1992, Novick 1989), with similar affinity to IL-6. Upon interaction with IL-6, sIL-6R doesn't behave as antagonist, instead it increases the circulating half life of IL-6 and at the same time activates the signaling pathway in cells where IL-6R is not expressed but gp130 is. This signaling pathway activated by IL-6: sIL-6R is known as the trans-signaling mechanism. The ubiquitous expression of gp130 suggests that the IL-6 trans-signaling pathway can activate all or most of the cell types in the body. A soluble form of cellular gp130 acts as an antagonist for IL-6 signaling pathway.
Preclinical studies have shown the role of cytokines in various inflammatory diseases and therefore these have become major therapeutic targets. There are several anti-TNF-α agents in the market that are broadly used to reduce inflammation. Since these are not effective in all patients, there is a need to explore other cytokines for their therapeutic role during inflammation such as IL-6. An anti-IL-6R antibody, tocilizumab, is currently used for treating rheumatoid arthritis.
Aptamers are oligonucleotides that bind their targets with high affinity and specificity. Aptamers may be selected using the SELEX (systematic evolution of ligands by exponential enrichment) method. Slow off rate modified aptamers (SOMAmers) are selected from random libraries containing functional groups absent in natural DNA (Gold et al, 2010, PLoS ONE 5(12): e15004). In some instances, these novel base modifications may mediate hydrophobic interactions between the aptamer and target, leading to significant improvement in binding affinity.